SPID#: 20 Since HIV-1 does not consistently cause disease in nonhuman species, there is no animal model system to evaluate the efficacy of strategies aimed at preventing or ameliorating disease caused by this virus. Since the virus envelope is thought to play a major role in pathogenesis, chimeric simian-human immunodeficiency viruses (SHIV) consisting of the core of SIVmac and the envelope of HIV-1 have been constructed, but have not proven to be pathogenic. We have recently developed a SHIV that is pathogenic in pig-tailed macaques. This is the first model in which primates inoculated with a lentivirus bearing the HIV-1 envelope developed loss of CD4+ T cells and AIDS. SHIV was passaged serially in cohorts of 2 macaques each, using bone marrow to bone marrow transfers at 5, 5, and 16 weeks, respectively. The virus became more virulent with each passage. Virus replication was controlled effectively by CD8+ T cells in animals in passages 1 and 2, but not in animals in passages 3 and 4. Virus resurgence, similar to that seen in HIV-1 infected people, developed in the latter animals and was evident as high virus burden in T cells in blood O. and lymphoid tissues, plasma viremia and infection in the CNS. Three of four animals in the last two passages developed CD4+ T cell loss. In one animal, the CD4+ T cell count decreased from 2,000 to 35 cells per ml in 26 weeks with development of AIDS. Two other animals have also developed a second phase of increasing virus burdens, similar to that seen in the fatal case. All animals developed neutralizing antibodies to the virus. Sequence analysis of the env gene of the pathogenic virus has shown the basis sequence pattern of the gp120 of HIV-1 HXB2, but with multiple mutations, including including some in the V3 loop. The availability of a pathogenic SHIV will be an asset to the development and testing of anti-HIV-1 drugs and vaccines.